Today, dependence upon drugs of addiction causes major health problems worldwide. For example, alcohol abuse and alcohol dependency can cause liver, pancreatic and kidney disease, heart disease, including dilated cardiomyopathy, polyneuropathy, internal bleeding, brain deterioration, alcohol poisoning, increased incidence of many types of cancer, insomnia, depression, anxiety, and even suicide. Heavy alcohol consumption by a pregnant mother can also lead to fetal alcohol syndrome, which is an incurable condition. Additionally, alcohol abuse and alcohol dependence are major contributing factors for head injuries, motor vehicle accidents, violence and assaults, and other neurological and other medical problems.
Another major health problem is caused by cocaine abuse. Physical effects of cocaine use include constricted blood vessels, dilated pupils, and increased temperature, heart rate, and blood pressure. A user of cocaine can experience acute cardiovascular or cerebrovascular emergencies, such as a heart attack or stroke, potentially resulting in sudden death. Other complications associated with cocaine use include disturbances in heart rhythm, chest pain and respiratory failure, seizures and headaches, and gastrointestinal complications such as abdominal pain and nausea. Because cocaine has a tendency to decrease appetite, many chronic users can become malnourished. Repeated use of cocaine may lead to a state of increasing irritability, restlessness, and paranoia. This can result in a period of full-blown paranoid psychosis, in which the user loses touch with reality and experiences auditory hallucinations.
Moreover, it is well known that the concurrent abuse of cocaine and alcohol is common. It has been found that the combination of cocaine and alcohol exerts more cardiovascular toxicity than either drug alone in humans.
Historically, treating alcohol dependence and cocaine dependence largely involved attempts to persuade patients to withdraw from use of alcohol and/or cocaine voluntarily (behavioral therapy). However, alcohol and cocaine are all highly addictive substances, and dependence upon such drugs can be harder to break and is significantly more damaging than dependence on most other addictive substances. In particular, cocaine dependence is typically seen to be a chronic relapsing disorder.
Accordingly, there has been much interest in the scientific community in attempting to find substances that could be employed to ameliorate alcohol dependency and cocaine dependency. Two compounds that have previously been employed for the treatment of alcohol abuse are known as disulfuram (Antabuse™) and cyanamide. Additionally, it has been recently proposed that disulfuram can be used for the treatment of cocaine dependency (for example, see Bonet et al., Journal of Substance Abuse Treatment, 26 (2004), 225-232).
More recently it has been shown that a compound known as daidzein is effective in suppressing ethanol intake. Daidzein is the major active component obtained from extracts of Radix puerariae, a traditional Chinese medication that suppresses ethanol intake in Syrian golden hamsters. See Keung, W. M. and Vallee, B. L. (1993) Proc. Natl. Acad. Sci. USA 90, 10008-10012 and Keung, W. M., Klyosov, A. A., and Vallee, B. L. (1997) Proc. Natl. Acad. Sci. USA 94, 1675-1679, and U.S. Pat. Nos. 5,624,910 and 6,121,010.
It has been shown that daidzin is an isoflavone of the formula:
Removal of the sugar provides a compound known as daidzein, which has also been shown to be effective in suppressing ethanol uptake.

U.S. Pat. Nos. 5,624,910 and 6,121,010 disclosed ether derivatives of daidzin, which were shown to be effective in treating ethanol dependency. Daidzin and its analogs were shown to be potent and selective inhibitors of human mitochondrial aldehyde dehydrogenase (ALDH-2), which is an enzyme involved in the major enzymatic pathway responsible for ethanol metabolism in humans. It was also found that daidzin analogues that inhibit ALDH-2 but also inhibit the monamine oxidase (MOA) pathway were the least effective antidipsotropic activity.
In U.S. Provisional Patent Application Ser. No. 60/834,083 and 60/846,428, novel isoflavone derivatives were disclosed that are ALDH-2 inhibitors with little effect on the MOA pathway, and are useful for the treatment of alcohol dependency and cocaine dependency, and, in particular, ameliorate the tendency of cocaine abusers to relapse.
We have now found quinazolinone derivatives that have similar properties. Surprisingly, it has also been found that ALDH-2 inhibitors, and the quinazolinone derivatives of the invention in particular, are also useful for the treatment of tobacco dependency. Addiction to tobacco is estimated by the National Institute on Drug Abuse to kill nearly 500,000 Americans every year. This total represents about 1 in 6 of all deaths in the U.S. caused by any means, and is more than the total of deaths caused by use of alcohol, cocaine, heroin, suicide, car accidents, fire and AIDS combined. As is well known, the primary addictive component of tobacco is nicotine, which is a highly addictive drug—it activates reward pathways in the brain that regulate feelings of pleasure. That is, nicotine increases levels of the neurotransmitter dopamine in the brain, which provides pleasurable sensations to the smoker.